Project Summary/Abstract This proposal brings together a top team with diverse and complementary expertise to develop a novel therapeutic agent based on a newly described serum protein, renalase (RNLS) to treat acute pancreatitis (AP). This protein has a novel protective effect in models of acute tissue injury, including AP. AP affects more than 250,000 people/year in the USA and can cause death in 20-30% of those with severe disease. It is the most common reason for hospitalization in the USA for individuals with gastrointestinal disease. RNLS is produced in the kidneys and other tissues, including the pancreas. Initial data show that: 1) Serum RNLS rapidly decreases soon after the onset of AP in a murine model and in humans, thus suggesting that RNLS has biomarker potential; 2) Genetic deletion of RNLS increases the severity of experimental acute murine pancreatitis; 3) Human recombinant research grade RNLS (hrRNLS) reduces pancreatitis responses in isolated murine pancreatic acinar cells; 4) Exogenous hrRNLS significantly reduces the severity of acute murine pancreatitis in vivo when given either as pretreatment or two hours after the onset of disease. The full-length hrRNLS protein was more efficacious in in vitro and in vivo AP models than hrRNLS peptides. These findings suggest that hrRNLS will have a protective role in AP. The proposed studies will examine research grade hrRNLS without an affinity tag present in previous drug supply synthesized in E. coli. We will test hrRNLS in mild (cerulein) and severe disease (arginine) AP models. The studies will determine the concentration-dependent effects and the relative effects of route (subcutaneous and IV) to reduce key measures of AP. hrRNLS will be given prior to the onset of injury (prophylactic) or after onset (therapeutic) of AP. In addition to quantifying biochemical and histologic parameters of AP in the pancreas and blood, the kidney and lung (also damaged in AP) will be examined for injury in male and female mice. Since severe pain is a major sequela of AP, hrRNLS effects to reduce sensitization to thermal and mechanical stimuli will be assessed. Pharmacokinetics of both routes will be examined. Initial toxicity studies of hrRNLS will be performed to determine its therapeutic index. Lastly, hrRNLS will be produced under GMP conditions and used in additional pharmacological studies towards an IND. Success in this project would advance hrRNLS as the potential 1st to market drug to treat AP.